The factors underlying the formation of long-lived antibody secreting cells (ASCs) or plasma cells are unknown. The main objective of this R21 application is to establish whether ASCs that form during the earliest phases of the humoral immune response to T cell dependent (TD) and T cell independent (TI) antigens are long-lived. The proposed experiments will follow from preliminary data suggesting that both TD and TI antigens elicit the formation of long-lived ASCs. Additional experiments will test whether ASCs that form in response to T cell independent antigen require migration into the bone marrow to become long-lived. We will address these questions using a combination of normal and genetically manipulated mouse lines. Specifically we will: 1) Define the lifespan of early ASCs produced via primary TI and TD antigens, and 2) Define the lifespan of TI-1 antigen-induced ASCs retained in the spleen. PUBLIC HEALTH RELEVANCE: The factors underlying the generation of long-lived antibody secreting plasma cells are not understood. Our studies will challenge current dogma that T cell independent antigens fail to induce the formation of long-lived plasma cells. These studies have direct implications for therapeutic strategies to combat antibody-mediated autoimmune diseases.